Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep;15(3):359-386.
doi: 10.1007/s11481-020-09944-5. Epub 2020 Jul 21.

The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections

Jatin Machhi  1 , Jonathan Herskovitz  1   2 , Ahmed M Senan  3 , Debashis Dutta  4 , Barnali Nath  5 , Maxim D Oleynikov  1 , Wilson R Blomberg  1 , Douglas D Meigs  1 , Mahmudul Hasan  6 , Milankumar Patel  1 , Peter Kline  7 , Raymond Chuen-Chung Chang  8 , Linda Chang  9 , Howard E Gendelman  10   11   12 , Bhavesh D Kevadiya  13   14
Affiliations
Review

The Natural History, Pathobiology, and Clinical Manifestations of SARS-CoV-2 Infections

Jatin Machhi et al. J Neuroimmune Pharmacol. 2020 Sep.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2, is a positive-sense single-stranded RNA virus with epithelial cell and respiratory system proclivity. Like its predecessor, SARS-CoV, COVID-19 can lead to life-threatening disease. Due to wide geographic impact affecting an extremely high proportion of the world population it was defined by the World Health Organization as a global public health pandemic. The infection is known to readily spread from person-to-person. This occurs through liquid droplets by cough, sneeze, hand-to-mouth-to-eye contact and through contaminated hard surfaces. Close human proximity accelerates SARS-CoV-2 spread. COVID-19 is a systemic disease that can move beyond the lungs by blood-based dissemination to affect multiple organs. These organs include the kidney, liver, muscles, nervous system, and spleen. The primary cause of SARS-CoV-2 mortality is acute respiratory distress syndrome initiated by epithelial infection and alveolar macrophage activation in the lungs. The early cell-based portal for viral entry is through the angiotensin-converting enzyme 2 receptor. Viral origins are zoonotic with genomic linkages to the bat coronaviruses but without an identifiable intermediate animal reservoir. There are currently few therapeutic options, and while many are being tested, although none are effective in curtailing the death rates. There is no available vaccine yet. Intense global efforts have targeted research into a better understanding of the epidemiology, molecular biology, pharmacology, and pathobiology of SARS-CoV-2. These fields of study will provide the insights directed to curtailing this disease outbreak with intense international impact. Graphical Abstract.

Keywords: Acute respiratory distress syndrome (ARDS); Angiotensin-converting enzyme 2 (ACE-2); Coronavirus disease 2019 (COVID-19); Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

PubMed Disclaimer

Figures

None
Graphical Abstract
Fig. 1
Fig. 1
Timeline of the global COVID-19 pandemic. a The timeline spans December 31st, 2019, to July 12th, 2020. It shows the significant events related to the number of cases and deaths globally. b As of July 12th, 2020, the representative world map shows the global distribution and the incidence of reported COVID-19 cases in each country. Clusters of pneumonia that had unknown origins were first reported from Wuhan on December 31st, 2019, to the China National Health Commission. On January 13th, 2020, the WHO reported the first cases outside of China in Thailand. The virus was named SARS-CoV-2 by the WHO on February 11th, 2020, and the disease was named COVID-19. On February 14th, 2020, Africa had its first confirmed case of coronavirus after a person in Egypt tested positive for the disease. In late February and early March, multiple international reports of SARS-CoV-2 confirmed over 82,000 people had been infected and over 2800 patients had died worldwide. The WHO declared COVID-19 officially a pandemic on March 11, 2020, as the viral disease swept into at least 114 countries and killed more than 4000 people. When Italy was the epicenter of the COVID-19 pandemic, roughly 7000 newly infected coronavirus cases were registered per day in the country on March 21st, 2020. Seven days later the number climbed to >600,000 cases with the death toll reaching 27,000. However, the true scale of the outbreak was thought to be significantly higher. Confirmed worldwide infections reached 1,000,000 with a global death toll of 50,000 on April 1st, 2020. Within the next 2 weeks, the United States reported 500,000 cases registered and a death toll surpassing Italy’s with 19,468 deaths. Throughout April, U.S. officials alleged that China was underreporting the total number of cases and deaths; on April 25th, 2020, there were no new cases and death reports for 10 days in a row, while the global death toll surpassed around 200,000. SARS-CoV-2 is continuing to spread across the world, with approximately 12.7 million confirmed cases in 213 countries. More than 560,000 people have died. The United States alone has more than 3.3 million confirmed cases, significantly more than the total confirmed cases reported by any other country (the next highest being Brazil with more than 1.8 million) as of July 12th 2020
Fig. 2
Fig. 2
SARS-CoV-2 transmission. Intra-species and inter-species dissemination of coronavirus. Initial hosts include bats, birds, and rats. COVID-19 is a member of the B lineage in the beta-coronavirus family, of which SARS-CoV-1 also descended. The WHO has characterized COVID-19 as a pandemic. As the virus spreads, so too does misinformation about its origins. The World Health Organization has categorized COVID-19 as a pandemic considering its spread far and wide. The spread of zoonotic disease from species that it evolved with to a new host is exacerbated by wildlife trafficking, habitat destruction, and climate change. These threats bring humans and animals closer together. Coronavirus is just an example of a string of pathogens that have come from wildlife trafficking, including SARS, Ebola, Bird Flu, and many more. In the case of wildlife trafficking and poaching, animals are hunted, trapped, and taken to markets to be sold for traditional medicine, food, and the pet trade. The wild animals can harbor diseases that can make other animals, including humans, sick. Wildlife trade markets facilitate viral transmission. They allow multiple species to be in proximity that otherwise would not come into prolonged contact with one another, which could be a factor for virulent strains of pathogens spreading to humans. Additionally, human capture of wildlife and incursion into natural wildlife habitats allow viruses to jump the species barrier. Addressing the legal trade and illegal trafficking of wild animals will help to stop the spread of zoonotic pathogens. Closing wildlife markets and controlling wildlife poaching would forestall the spread of zoonotic pathogens while also addressing a significant driver of species annihilation. China has recently shut all of its wild-life animal markets and this step has been applauded globally
Fig. 3
Fig. 3
SARS-CoV-2 life cycle in virus susceptible host cells. ACE-2 binds to the receptor-binding domain (RBD) of spike proteins (S) (1), allowing for fusion with the host cell membrane (2). Positive sense single-stranded RNA is released (3), partially translated into SARS-CoV-2 polymerase protein (4–5), and transcribed (6). The resultant subgenomic RNA translational S, M, and E proteins are taken to the host cell ER membrane (7) and later combined with nucleocapsid protein (N) (8). Post Golgi processing, all elements are incorporated into a mature virion (9) and traffic to the cell membrane for exocytosis (10) of newly budded SARS-CoV-2 particles (11)
Fig. 4
Fig. 4
ARDS in severe SARS-CoV-2 infections. Development of SARS-CoV-2 infection in the lower lung results in fluid collection within the bronchioles, which disrupts protective surfactant coatings typically released by type II pneumocytes. This leads to alveolar instability and the sloughing of endothelial cells. Additionally, ARDS causes a hyperactive immune response, localizing neutrophils, and increasing cytokine release, which leads to the accumulation of reactive oxygen species, cell debris, and proteases. Edema results from protein accumulation in interstitial space and vasoconstriction via platelet activation, which further decreases oxygen exchange capacity
Fig. 5
Fig. 5
Pathophysiology of SARS-CoV-2 systemic infection. Infection initiates in the upper respiratory tract and progresses to lower regions of the lung in severe cases. Respiratory droplets carrying SARS-CoV-2 infect epithelial and endothelial cells, neurons, microglia, and lung macrophages containing angiotensin-converting enzyme 2 (ACE-2). Viral replication and release of damage-associated molecular patterns induce pyroptosis, causing a dysfunctional innate immune response. Release of pro-inflammatory agents can induce a cytokine storm, increasing vasodilation, capillary permeability, and hypoxemia that can often lead to multiple organ failure
Fig. 6
Fig. 6
SARS-CoV-2 and Kawasaki disease. SARS-Cov-2 infected pediatric patients show multi-system inflammatory syndrome with symptoms overlapping to the Kawasaki disease. Patients show a diffuse maculopapular rash with swelling on the hands and feet. Extra-reddish tongue and lips and bulbar conjunctivitis are symptoms. Disease, while of unknown cause, affected children under 5 years old. Relationship between Kawasaki disease and SARS-CoV-2 infection is noteworthy. The Kawasaki disease with SARS-CoV-2 infection is characterized by vasculitis with fever and generalized rash not responsive to conventional anti-inflammatory medicines. Associated signs and symptoms include enlarged lymph nodes, inflamed lips, palms, eyes, and soles of the feet. In weeks after disease onset, there is exfoliation of the hands and feet. Coronary artery aneurysms can form with an autoimmune response
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdullah AS, Tomlinson B, Cockram CS, Thomas GN. Lessons from the severe acute respiratory syndrome outbreak in Hong Kong. Emerg Infect Dis. 2003;9:1042–1045. - PMC - PubMed
    1. Ahmed F, Ahmed N, Pissarides C, Stiglitz J. Why inequality could spread COVID-19. Lancet Public Health. 2020;5:e240. - PMC - PubMed
    1. Al Saiegh F, Ghosh R, Leibold A, Avery MB, Schmidt RF, Theofanis T, Mouchtouris N, Philipp L, Peiper SC, Wang ZX, Rincon F, Tjoumakaris SI, Jabbour P, Rosenwasser RH, Gooch MR (2020) Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke. J Neurol Neurosurg Psychiatry - PubMed
    1. Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio. 2013;4:e00524–e00513. - PMC - PubMed
    1. Archer T (2020) Coronavirus cancellations and reactions in sports. ESPN. https://www.espn.com/espn/story/_/id/28871525/coronavirus-cancellations-...

Publication types

LinkOut - more resources

-